When a cell receives a stimulus from outside, its intracellular signaling pathway is activated to induce proliferation, differentiation, apoptosis and the like of the cell. Tyrosine phosphorylation of intracellular proteins acts an extremely important role in various phases of the signaling pathway, and the state of tyrosine phosphorylation of each protein is always regulated by dynamic equilibrium of delicate balance of two families of enzymes, tyrosine kinase (PTK) and tyrosine phosphatase (PTP). It is known that this tyrosine phosphorylation of proteins is involved in controlling the efficiency of neural circuit formation and neurotransmission in brains (SEITAI NO KAGAKU Vol. 48, No. 6, 534–538, (1997); PROTEIN, NUCLEIC ACID AND ENZYME Vol. 43, No. 8, 1136–1143 (1998)), and is important for the formation and the maintenance of the functions in an immune system and other organs (PROTEIN, NUCLEIC ACID AND ENZYME Vol. 43, No. 8, 1131–1135 (1998)). On the other hand, it is reported that the abnormal tyrosine phosphorylation of proteins is involved in defects in neural circuit formation, disturbance of memory and learning, abnormal apoptosis, tumorigenesis or the like (PROTEIN, NUCLEIC ACID AND ENZYME Vol. 43, No. 8, 1186–1192 (1998)).
To date, more than 80 kinds of PTP have been identified, and it is presumed that the number of genes of PTP in human would reach to 500. Similar to PTK, PTP is classified into two types: a receptor type and a non-receptor type. A receptor-type PTP has two or one enzymic domain intracellularly, and is classified into several groups according to the characteristics of its extracellular domain. PTPζ, which has a carbonic anhydrase domain in N-terminal, has been identified as a receptor-type tyrosine phosphatase specific to the central nervous system. The inventors of the present invention have reported that PTPζ is a receptor of growth factors including pleiotrophin and midkine (J. Biol. Chem. 271, 21446–21452, 1996; J. Cell Biol. 142, 203–216, 1998; J. Biol. Chem. 274, 12471–12479, 1999). In addition, PTPζ is known to interact with cell adhesion molecules which belong to the immunogloblin super family, such as N-CAM, and is thought to be responsible for important functions in differentiation, migration and neurotransmission of neurons. The present inventors have already generated a PTPζ gene-deficient mouse and reported that PTPζ has expressed in both neurons and astrocytes (Neuroscience Letters 274, 135–138, 1998). The PTPζ gene-deficient mouse has grown and propagated normally, and no major morphologic abnormality has been identified. However, the physiological role of PTPζ has been hardly elucidated so far.
Recently, Hirayama has shown a possibility that PTPζ functions as a receptor of VacA, an exotoxin secreted by Helicobacter pylori which is well known as a cause of gastric ulcer, through a test system using cell lines (J. Biol. Chem. 274, 36693–36699, 1999). VacA, a toxin of Helicobacter pylori, is detected in about 90% of patients who suffer from acute gastritis or gastric ulcer, and it is reported that a mouse orally administered with VacA, a toxin extracellulary secreted by Helicobacter pylori, shows the onset of acute gastritis.
The clarification of in vivo role of PTPζ, whose physiological function has been conventionally unknown, makes it possible to provide findings and experimental materials that lead to the elucidation of onset mechanisms of diseases related to the physiological function of PTPζ, and to the development of remedies of the diseases. An object of the present invention is to provide a remedy for dysfunction of central monoamine pathway, a method for screening a PTPζ inhibitor or activator, which is useful as a remedy for gastric ulcer caused by Helicobacter pylori or the like, as a non-human model animal being hyposensitive to a central stimulant drug (an addictive drug) and as a non-human model animal being hyposensitive to VacA, a toxin of Helicobacter pylori, or the like, by utilizing the physiological function of PTPζ identified with the use of a PTPζ gene-deficient mouse.
As aforementioned, the present inventors have already generated the mouse with the use of a homologous recombination technique, but it was difficult to eliminate the influence of other genes from the mouse because the mouse was a hybrid wherein chromosomes of two lines of mouse, that is, 129/Sv and C57BL/6J, were mixed. Therefore, a pure line mouse was sufficiently backcrossed (4 generations) to be suitable for analyzing the physiological function of PTPζ, and a PTPζ gene-deficient mouse from which the influence of other genes was eliminated was generated. By comparative analysis of a mouse whose function of gene DNA that encodes the PTPζ was deficient on its chromosome and a wild type mouse, it is revealed for the first time that the PTPζ gene-deficient mouse, which has grown and propagated normally, and where no major morphologic abnormality has been identified, has dysfunction of central monoamine pathway, such as changes in the level of central monoamine metabolism, hyposensitivity to a stimulant drug (methamphetamine), dysfunction of mesolimbic dopamine pathway, delay in acclimating to new circumstances and increase in stress-responsiveness. Further, it was found that PTPζ, which is thought to be a receptor of VacA, a toxin of Helicobacter pylori, is expressed in gastric epithelial cell layer of a mouse. The present invention has thus been completed.